EP0242230B1 - Pyrido [1,2-a] pyrimidine derivatives - Google Patents

Pyrido [1,2-a] pyrimidine derivatives Download PDF

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Publication number
EP0242230B1
EP0242230B1 EP87303424A EP87303424A EP0242230B1 EP 0242230 B1 EP0242230 B1 EP 0242230B1 EP 87303424 A EP87303424 A EP 87303424A EP 87303424 A EP87303424 A EP 87303424A EP 0242230 B1 EP0242230 B1 EP 0242230B1
Authority
EP
European Patent Office
Prior art keywords
pyrido
oxo
acetyl
propylphenoxymethyl
hydroxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP87303424A
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German (de)
English (en)
French (fr)
Other versions
EP0242230A2 (en
EP0242230A3 (en
Inventor
Naoto Matsuishi
Michiaki Amano
Yoshio Nakagawa
Norihiko Kakehi
Toshio 2-19-310 Washimiyadanchi Kawashima
Shigeki C/O Setagaya's Company Omura
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mitsubishi Tanabe Pharma Corp
Original Assignee
Tokyo Tanabe Co Ltd
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Publication date
Application filed by Tokyo Tanabe Co Ltd filed Critical Tokyo Tanabe Co Ltd
Publication of EP0242230A2 publication Critical patent/EP0242230A2/en
Publication of EP0242230A3 publication Critical patent/EP0242230A3/en
Application granted granted Critical
Publication of EP0242230B1 publication Critical patent/EP0242230B1/en
Anticipated expiration legal-status Critical
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to pyrido[1,2-a]pyrimidine derivatives and physiologically acceptable salts thereof, which have a marked antagonistic effect on the slow-reacting substance of anaphylaxis (hereinafter abbreviated as SRS-A) and, therefore, are useful in the treatment of Type I allergic diseases induced by SRS-A.
  • SRS-A slow-reacting substance of anaphylaxis
  • SRS-A is strongly effective in causing contraction of smooth muscle and constitutes a substance responsible for Type I allergic diseases, particularly bronchial asthma and allergic rhinitis [Quarterly Journal of Experimental Physiology, Vol. 30, p. 121, 1940].
  • Leukotriene D 4 has been found to be a representative active component of this subtance and the presence of an inhibitory effect on the in vivo activity of leukotriene D 4 is now considered to be a criterion of the usefulness of drugs for the treatment of Type I allergic diseases induced by SRS-A [Nature, Vol. 288, p. 484, 1980].
  • Drugs useful for the treatment of Type I allergic diseases induced by SRS-A are roughly divided into two types: drugs of the SRS-A release suppression type which act to prevent the release of SRS-A from mast cells or basophils and thereby inhibit its activity indirectly, and drugs of the SRS-A antagonistic type which act to antagonize the released SRS-A in the living body and thereby inhibit its activity directly.
  • drugs of the SRS-A release suppression type are basically used for the purpose of preventing the induction of allergic attacks by SRS-A and generally tend to lack effectiveness immediately after the onset of an attack. That is, they often fail to exhibit the so-called rapid-acting property. In recent years, therefore, it has been eagerly desired from the viewpoint of an immediate effect on allergic attacks to develop a satisfactorily effective drug of the SRS-A antagonistic type.
  • Compound A 9-Benzyloxy-4-oxo-pyrido[1,2-a]pyrimidine-3-carboxylic acid
  • Compound A 9-Benzyloxy-4-oxo-pyrido[1,2-a]pyrimidine-3-carboxylic acid
  • a pharmaceutical composition useful for the treatment of allergic diseases comprising, as an active ingredient, a pyrido[1,2-a]pyrimidine derivative of the above general formula [I] and/or a physiologically acceptable salt thereof.
  • a pyrido[1,2-a]pyrimidine derivative of the above general formula [I] and physiologically acceptable.'- salts thereof will hereinafter be referred to generically as "the present compounds [I]".
  • the present compounds [I] can be prepared by hydrolyzing ester derivatives of the general formula where R and n are as previously defined, and R' is a lower alkyl group, with an excess of an acid or an alkali.
  • Acids useful forthis purpose include inorganic acids such as sulfuric acid, hydrochloric acid, etc.
  • Useful alkalis include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc., and alkali metal carbonates'such as sodium carbonate, potassium carbonate, etc.
  • the hydrolysis may be carried out in a water-containing organic solvent at a temperature of 0 to 150°C, preferably 20 to 100°C, for a period of time ranging from 1 minute to 72 hours.
  • Organic solvents suitable for use in the hydrolysis include lower alcohols such as methanol, ethanol; organic acids such as acetic acid, formic acid; and ethers such as tetrahydrofuran, dioxane.
  • Physiologically acceptable salts of the pyrido[1,2-a]pyrimidine derivatives represented by the above general formula [I] can be prepared by reacting the corresponding pyrido[1,2-a]pyrimidine derivative with an alkali metal or alkaline earth metal hydroxide (such as sodium hydroxide, potassium hydroxide, calcium hydroxide), an alkali metal or alkali metal or alkaline earth metal carbonate (such as sodium carbonate, potassium carbonate, calcium carbonate), an organic amine (such as ethanolamine, methylephedrine) or ammonia in water, a lower alcohol or a mixture thereof.
  • alkali metal or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide, calcium hydroxide
  • an alkali metal or alkali metal or alkaline earth metal carbonate such as sodium carbonate, potassium carbonate, calcium carbonate
  • an organic amine such as ethanolamine, methylephedrine
  • Lower alcohols useful for this purpose include methanol
  • An ester derivative represented by the above formula [II] can be prepared by condensing 1 mole of a compound of the general formula where R, R' and n are as previously defined and X is a chlorine or bromine atom, with 1 to 6 moles of 2,4-di- hydroxy-3-n-propylacetophenone in the presence of an acid acceptor.
  • Acid acceptors useful for this purpose include alkali metal carbonates such as sodium carbonate, potassium carbonate, and alkali metal hydroxides such as sodium hydroxide, potassium hydroxide.
  • alkali metal carbonates such as sodium carbonate, potassium carbonate
  • alkali metal hydroxides such as sodium hydroxide, potassium hydroxide.
  • potassium iodide may also be present as a reaction accelerator.
  • Suitable reaction solvents include acetone, methyl ethyl ketone, diethyl ketone, cyclohexanone, dimethylformamide and dimethyl sulfoxide, as well as mixtures of two or more such solvents.
  • the reaction may be carried out by heating the reaction mixture at a temperature of 50 to 110°C for a period of time ranging from 1 minute to 72 hours.
  • ester derivatives [II] prepared in the above-described manner also have practically as good an antagonistic effect on SRS-A as their corresponding carboxylic acids.
  • a compound represented by the above formula [III] may be prepared (1) by halogenating a compound of the general formula where R, R' and n are as previously defined, with the aid of N-bromosuccinimide or N-chlorosuccinimide; (2) by halogenating a compound of the general formula where R, R' and n are as previously defined, with the aid of a halogenating agent such as thionyl chloride, phosphoryl chloride, phosphoryl bromide, phosphorus trichloride, phosphorus tribromide or the like; or (3) by reacting atompound of the general formula where R, R' and n are as previously defined, with a mixture of phosphoryl chloride or phosphoryl bromide and polyphosphoric acid to effect its ring closure and halogenation at the same time.
  • a halogenating agent such as thionyl chloride, phosphoryl chloride, phosphoryl bromide, phosphorus trichloride, phosphorus tribromide
  • leukotriene D 4 of the present compounds [I] was tested by using the terminal lieum excised from a male guinea pig of the Hartley strain. Specifically, the terminal ileum was suspended, under aerated conditions, in 10 ml of Tyrode's solution containing 5 x 10 -7 M atropine and 1 x 10 -6 M mepyramine. Then, a test compound and leukotriene D 4 (manufactured by Wako Junyaku Co., Ltd.) were successively added thereto with an interval of 30 seconds.
  • the degree of contraction of the ileum was measured with a Model TD-112S Isotonic Transducer (manufactured by Nippon Koden Co., Ltd.).
  • the test compound and leukotriene D 4 were used in such amounts as to give concentrations of 10- 9 to 10- 3 g/ml and 0.3 mg/ml, respectively.
  • the antagonistic effect on leukotriene D 4 of each test compound was evaluated in terms of the concentration of the test compound at which the ileum contraction reaction induced by leukotriene D 4 was inhibited by 50% (hereinafter referred to as IC so ). Specifically, at varying concentrations of each test compound, the percent inhibition degree of contraction was calculated from the measured degree of contraction of the ileum according to the following equation: '
  • test compounds used in these experiments were the compounds enumerated below and considered to be typical of the present compounds [I].
  • the designation given in parentheses after the chemical name of each compound means its tentative name as used herein and corresponds to the respective one of the examples which will be described later.
  • a respirator with a ventilation volume of 5-7 ml, a respiration rate of 70 per minute, and a pulmonary load pressure of 10 cmH 2 0; manufactured by Ugo Basile Biological Research Apparatus Co.
  • the volume of air overflowing through the branch of the cannula was measured by means of a Model 7020 Bronchospasm Transducer (manufactured by Ugo Basile Biological Research Apparatus Co.) and recorded with a Model RM-6000 Polygraph (manufactured by Nippon Koden Co., Ltd.).
  • the tests were carried out as follows: Each guinea pig was treated by intravenous injection of 1 mg/kg of gallamine triethiodide. Then, 5 mg/kg of a test compound and 0.5 pg/kg of leukotriene D 4 were successively administered thereto through the cervical vein with an interval of 2 minutes, and the volume of air overflowing as a result of the induced airway constriction reaction was measured.
  • the test compound was used in the form of a solution in physiological saline containing sodium hydrogen carbonate, while leukotriene D 4 was used in the form of a solution in physiological saline.
  • the acute toxicity (LD 50 ) of several typical examples of the present compounds [I] was tested on 5- week-old male ddY strain mice and male SD strain rats.
  • the compounds of Examples 2 and 4 were selected as typical examples.
  • the LD so values of these two compounds were not less than 4.0 g/kg when administered orally, and not less than 100 mg/kg when administered intravenously.
  • rats their LD 50 values were not less than 4.0 g/kg when administered orally, and not less than 200 mg/kg when administered intravenously.
  • the present compounds [I] are useful for the treatment of SRS-A induced Type I allergic diseases including, in particular, bronchial asthma and allergic rhinitis.
  • the present compounds [I] may also be used as anti-ulcer agents, anti-inflammatory agents or drugs for the treatment of ischaemic heart diseases.
  • compositions may have a variety of dosage forms including injectable solutions, tablets, capsules, powders, fine granules, granules, liquors, suspensions and emulsions.
  • the pharmaceutical carriers can be of any of various pharmaceutical carriers usually used in such dosage forms, and examples thereof include excipients, binders and disintegrants, such as corn starch, dextrin, ⁇ -, ⁇ - or y-cyclodextrin, glucose, lactose, sucrose, methylcellulose, calcium carboxymethylcellulose, crystalline cellulose, magnesium stearate, sodium alginate, Witepsol W35, Witespol E85, polyvinyl alcohol, light silicic acid anhydride, etc.; lubricants such as talc, stearic acid, waxes, hydroxypropylcellulose, boric acid, etc.; coating agents such as shellac, cellulose acetic phthalate, polyvinyl acetal diethyl- aminoacetate, etc.; solubilizing agents such as glycerol, propylene glycol, mannitol, etc.; emulsifying or suspending agents such as polyoxyethylene stearate, polyoxyethylene cety
  • the present compound [I] should be present in such an amount that the daily dose of the active ingredient is in the range of 0.002 to 60 mg/kg, preferably 0.02 to 10 mg/kg, for purposes of oral administration or in the range of 1 to 1000 p/kg, preferably 10 to 200 p/kg, for purposes of intravenous injection.
  • the thirteen compounds enumerated below were prepared in substantially the same manner as described above, except that the [9-bromomethyl-4-oxo-pyrido[1,2-a]pyrimidin-3-yl]acetic acid ethyl ester was replaced by each of the corresponding compounds [III] and that the molar ratio of reactants and the reaction conditions were suitably modified. Thus, these compounds were obtained in a yield ranging from 41% to 91%.
  • Infrared absorption spectrum (cm -1 , KBr): 2600-2500, 1720, 1700, 1635, 1275.
  • Example 3-6 The compounds of the following Example 3-6 were prepared in substantially the same manner as described in Example 2 above, except that the [9-(4-acetyl-3-hydrox-2-n-propylphenoxymethyl)-4-oxo- pyrido[1,2-a]pyrimidin-3-yl]acetic acid ethyl ester (1.85 mmoles) was replaced by each of the corresponding ester derivatives [II] (1.85 mmoles).
  • Infrared absorption spectrum (cm-', KBr): 2700-2500, 1730, 1675, 1635, 1275.
  • Infrared absorption spectrum (cm-', KBr): 2700-2500, 1720, 1680, 1625, 1270.
  • Infrared absorption spectrum (cm-', KBr): 2700-2500, 1715, 1695, 1630, 1270.
  • Infrared absorption spectrum (cm-', KBr): 2700-2500, 1720, 1680, 1625, 1270.
  • the above ingredients (1 )-(5) were blended together. After the addition of water, the resulting mixture was granulated and then dried. The granules so formed were adjusted to a predetermined size range, and the ingredient (6) was added thereto. The resulting mixture was compressed to form tablets each containing 10 mg of the active ingredient.
  • composition 2 (capsules) % by weight
  • the above ingredients were blended together and then granulated.
  • the granules so formed were filled into capsules, each of which contained 10 mg of the active ingredient.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pulmonology (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Numerical Control (AREA)
  • Adornments (AREA)
EP87303424A 1986-04-16 1987-04-16 Pyrido [1,2-a] pyrimidine derivatives Expired - Lifetime EP0242230B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP61086034A JPS62242682A (ja) 1986-04-16 1986-04-16 新規なピリド［１，２―ａ］ピリミジン誘導体及びその製造法
JP86034/86 1986-04-16

Publications (3)

Publication Number Publication Date
EP0242230A2 EP0242230A2 (en) 1987-10-21
EP0242230A3 EP0242230A3 (en) 1989-01-11
EP0242230B1 true EP0242230B1 (en) 1990-10-03

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ID=13875382

Family Applications (1)

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EP87303424A Expired - Lifetime EP0242230B1 (en) 1986-04-16 1987-04-16 Pyrido [1,2-a] pyrimidine derivatives

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US (1) US4798832A (enrdf_load_stackoverflow)
EP (1) EP0242230B1 (enrdf_load_stackoverflow)
JP (2) JPS62242682A (enrdf_load_stackoverflow)
AT (1) ATE57185T1 (enrdf_load_stackoverflow)
AU (1) AU601723B2 (enrdf_load_stackoverflow)
CA (1) CA1286665C (enrdf_load_stackoverflow)
DE (1) DE3765285D1 (enrdf_load_stackoverflow)
ES (1) ES2031889T3 (enrdf_load_stackoverflow)
GR (1) GR3000930T3 (enrdf_load_stackoverflow)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0311016A (ja) * 1989-06-09 1991-01-18 Tokyo Tanabe Co Ltd ピリド［１，２―ａ］ピリミジン誘導体の水性製剤
AU633584B2 (en) * 1989-06-15 1993-02-04 Tokyo Tanabe Company Limited Aerosols of pyrido(1,2-a)pyrimidine compounds
JPH0386825A (ja) * 1989-06-15 1991-04-11 Tokyo Tanabe Co Ltd ピリド［１，２―ａ］ピリミジン誘導体のエアロゾル剤
JPH05339150A (ja) * 1992-06-05 1993-12-21 Tokyo Tanabe Co Ltd 経口投与用ピリド［１，２−ａピリミジン誘導体の組成物

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1009233A (en) * 1972-04-17 1977-04-26 Harry L. Yale 9-SUBSTITUTED-4-OXOPYRIDO(1,2-.alpha.)-PYRIMIDINE-3-CARBOXYLIC ACIDS AND DERIVATIVES THEREOF
GB1583691A (en) * 1977-01-26 1981-01-28 Fisons Ltd Benzopyrans
US4122274A (en) * 1977-05-25 1978-10-24 Bristol-Myers Company 3-Tetrazolo-5,6,7,8-substituted-pyrido[1,2-a]pyrimidin-4-ones
HU184058B (en) * 1977-12-29 1984-06-28 Chinoin Gyogyszer Es Vegyeszet Process for preparing new compounds with nitrogen bridge head
US4209620A (en) * 1978-06-19 1980-06-24 Bristol-Myers Company Substituted 3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one derivatives having antiallergy activity
JPS57206920A (en) * 1981-06-15 1982-12-18 Yamazaki Mazak Corp Numerically controlled machine tool
US4661505A (en) * 1982-11-03 1987-04-28 Eli Lilly And Company Leukotriene antagonists
US4667055A (en) * 1983-12-29 1987-05-19 Merck Frosst Canada, Inc. Leukotriene antagonists
US4617407A (en) * 1984-08-30 1986-10-14 Merck Frosst Canada, Inc. Leukotriene antagonists
JPS63183581A (ja) * 1985-10-03 1988-07-28 Tokyo Tanabe Co Ltd ピリド〔１，２−ａ〕ピリミジン誘導体、その製造法及びそれを有効成分とするアレルギ−疾患治療薬

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Publication number Publication date
ES2031889T3 (es) 1993-01-01
EP0242230A2 (en) 1987-10-21
AU601723B2 (en) 1990-09-20
GR3000930T3 (en) 1991-12-10
ATE57185T1 (de) 1990-10-15
US4798832A (en) 1989-01-17
DE3765285D1 (de) 1990-11-08
JPS62242682A (ja) 1987-10-23
AU7109787A (en) 1987-10-22
JPH0615472B2 (ja) 1994-03-02
EP0242230A3 (en) 1989-01-11
JPH01193223A (ja) 1989-08-03
CA1286665C (en) 1991-07-23
JPH0374669B2 (enrdf_load_stackoverflow) 1991-11-27

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